Regulation of TH17 Responses by 3-secretase The recently recognized subset of Th17 effector T cells informs our understanding of both normal cellular immune responses as well as mechanisms leading to several autoimmune diseases. For example, we now know that Th17 cells are responsible for the clearance of several extracellular bacteria. Aberrant Th17 responses also play a critical role in a variety of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), collagen induced arthritis (CIA), irritable bowel disease (IBD) and psoriasis. Our preliminary data suggest 3-secretase inhibition (GSI) blocks Th17 development in vitro. The aims of this application are directed at determining how GSI blocks Th17 responses. In particular, we hypothesize that GSI blockade of Th17 may be due, at least in part, to the effects of GSI on Notch signaling and experiments designed to explore this are proposed in Aim 1. We also propose that GSI will block in vivo Th17 responses and this will result in amelioration of EAE and experiments to test this hypothesis are described in Aim 2. The data from this exploratory proposal will better inform us of the role of GSI in TH17 development and may reveal an essential role for targets of 3-secretase in regulating EAE. Public Health Relevance: The contributions of this research to human health are numerous. The biological system we investigate, the immune system, is critical to human health and the molecule we study, Notch, is necessary to mount a normal immune response. Equally important is the fact that Notch, when inappropriately expressed, can lead to autoimmunity and to cancer of the immune system.